Understanding how elevated intraocular pressure (IOP) damages optic nerve fibers will lead to new glaucoma therapies designated specifically to protect optic nerve fibers. To study this relationship, chronically elevated IOP has been produced in rats; resulting in progressive, regional degeneration of ganglion cell axons, optic never head cupping, and deposition of extracellular matrix components with the lamina cribrosa-all characteristics of the human disease. Quantitative ultrastructural analysis of cross sections from these optic nerves show that the remaining axons lose their normal, round profiles. This loss of axonal shape (atrophy), observed in eyes with mild IOP elevation, develops more rapidly with higher pressure, and is more pronounced in regions and nerves with greater axonal degeneration. The appearance of atrophy in pressure-induced optic nerve damage suggests a new hypothesis: elevated IOP damages optic nerves by creating a progressive axonal atrophy that leads eventually to degeneration. Understanding the nature of this atrophy and its relationship to degeneration will be key to understanding the mechanism of glaucomas optics nerve damage. This proposal will begin determining how IOP produces axonal atrophy by showing that it is regionally associated with axonal degeneration over a range of IOPs. Morphometric analysis will determine whether this atrophy is due to diminished numbers of neurofilaments and/or microtubules to alterations in their arrangement, or both. Interpreting these findings will be aided by dynamic measurements of cytoskeletal mRNA and protein production and slow axonal transport, both of which affect axonal volume. Using this multifaceted experimental approach, this proposal will determine which of the major processes governing axon size are affected by IOP, and lead to more specific hypothesis concerning the mechanism of pressure-induced atrophy and axonal degeneration in glaucoma.